RESUMO
Ruthenium (Ru) complexes are developed as latent emissive photosensitizers for cancer and pathogen photodiagnosis and therapy. Nevertheless, most existing Ru complexes are limited as photosensitizers in terms of short excitation and emission wavelengths. Herein, we present an emissive Ru(II) metallacycle (herein referred to as 1) that is excited by 808-nm laser and emits at a wavelength of â¼1,000 nm via coordination-driven self-assembly. Metallacycle 1 exhibits good optical penetration (â¼7 mm) and satisfactory reactive oxygen species production properties. Furthermore, 1 shows broad-spectrum antibacterial activity (including against drug-resistant Escherichia coli) as well as low cytotoxicity to normal mammalian cells. In vivo studies reveal that 1 is employed in precise, second near-infrared biomedical window fluorescent imaging-guided, photo-triggered treatments in Staphylococcus aureus-infected mice models, with negligible side effects. This work thus broads the applications of supramolecular photosensitizers through the strategy of lengthening their wavelengths.
Assuntos
Infecções Bacterianas , Complexos de Coordenação , Fotoquimioterapia , Fármacos Fotossensibilizantes , Rutênio , Animais , Antibacterianos/farmacologia , Bactérias , Infecções Bacterianas/diagnóstico , Complexos de Coordenação/farmacologia , Escherichia coli/efeitos dos fármacos , Luz , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Rutênio/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with minimal side effects in deep-seated tumors remains challenging. Herein, we introduce a novel self-assembled near-infrared-light-activated ruthenium(II) metallacycle, Ru1105 (λem = 1105 nm), as a first example of a Ru(II) supramolecular ICD inducer. Ru1105 synergistically potentiates immunomodulatory responses and reduces adverse effects in deep-seated tumors through multiple regulated approaches, including NIR-light excitation, increased reactive oxygen species (ROS) generation, selective targeting of tumor cells, precision organelle localization, and improved tumor penetration/retention capabilities. Specifically, Ru1105 demonstrates excellent depth-activated ROS production (â¼1 cm), strong resistance to diffusion, and anti-ROS quenching. Moreover, Ru1105 exhibits promising results in cellular uptake and ROS generation in cancer cells and multicellular tumor spheroids. Importantly, Ru1105 induces more efficient ICD in an ultralow dose (10 µM) compared to the conventional anticancer agent, oxaliplatin (300 µM). In vivo experiments further confirm Ru1105's potency as an ICD inducer, eliciting CD8+ T cell responses and depleting Foxp3+ T cells with minimal adverse effects. Our research lays the foundation for the design of secure and exceptionally potent metal-based ICD agents in immunotherapy.
Assuntos
Antineoplásicos , Neoplasias , Rutênio , Humanos , Rutênio/farmacologia , Espécies Reativas de Oxigênio , Morte Celular Imunogênica , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Lisossomos , Linhagem Celular TumoralRESUMO
High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy.
Assuntos
Nanopartículas , Neoplasias , Selênio , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fototerapia/métodos , Verde de Indocianina/toxicidade , Nanopartículas/química , Neoplasias/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Correction for 'Near-infrared metal agents assisting precision medicine: from strategic design to bioimaging and therapeutic applications' by Chonglu Li et al., Chem. Soc. Rev., 2023, 52, 4392-4442, https://doi.org/10.1039/D3CS00227F.
RESUMO
Metal agents have made incredible strides in preclinical research and clinical applications in recent years, but their short emission/absorption wavelengths continue to be a barrier to their distribution, therapeutic action, visual tracking, and efficacy evaluation. Nowadays, the near-infrared window (NIR, 650-1700 nm) provides a more accurate imaging and treatment option. Thus, there has been ongoing research focusing on developing multifunctional NIR metal agents for imaging and therapy that have deeper tissue penetration. The design, characteristics, bioimaging, and therapy of NIR metal agents are covered in this overview of papers and reports published to date. To start with, we focus on describing the structure, design strategies, and photophysical properties of metal agents from the NIR-I (650-1000 nm) to NIR-II (1000-1700 nm) region, in order of molecular metal complexes (MMCs), metal-organic complexes (MOCs), and metal-organic frameworks (MOFs). Next, the biomedical applications brought by these superior photophysical and chemical properties for more accurate imaging and therapy are discussed. Finally, we explore the challenges and prospects of each type of NIR metal agent for future biomedical research and clinical translation.
Assuntos
Diagnóstico por Imagem , Medicina de Precisão , Metais , Corantes Fluorescentes/química , Imagem Óptica/métodosRESUMO
Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~7â mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5â µM) compared with the clinical ICD inducer-oxaliplatin (300â µM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8+/CD4+ Tâ cell response and Foxp3+ Tâ cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy.
RESUMO
Albeit sonodynamic therapy (SDT) has achieved encouraging progress in microbial sterilization, the scarcity of guidelines for designing highly effective sonosensitizers and the intricate biofilm microenvironment (BME), substantially hamper the therapeutic efficacy against biofilm infections. To address the bottlenecks, we innovatively design a Ru(II) metallacycle-based sonosensitizer/sonocatalyst (named Ru-A3-TTD) to enhance the potency of sonotherapy by employing molecular engineering strategies tailored to BME. Our approach involves augmenting Ru-A3-TTD's production of ultrasonic-triggered reactive oxygen species (ROS), surpassing the performance of commercial sonosensitizers, through a straightforward but potent π-expansion approach. Within the BME, Ru-A3-TTD synergistically amplifies sonotherapeutic efficacy via triple-modulated approaches: (i) effective alleviation of hypoxia, leading to increased ROS generation, (ii) disruption of the antioxidant defense system, which shields ROS from glutathione consumption, and (iii) enhanced biofilm penetration, enabling ROS production in deep sites. Notably, Ru-A3-TTD sono-catalytically oxidizes NADPH, a critical coenzyme involved in antioxidant defenses. Consequently, Ru-A3-TTD demonstrates superior biofilm eradication potency against multidrug-resistant Escherichia coli compared to conventional clinical antibiotics, both in vitro and in vivo. To our knowledge, this study represents the pioneering instance of a supramolecular sonosensitizer/sonocatalyst. It provides valuable insights into the structure-activity relationship of sonosensitizers and paves a promising pathway for the treatment of biofilm infections.
Assuntos
Antioxidantes , Neoplasias , Humanos , Espécies Reativas de Oxigênio , Antibacterianos/farmacologia , Biofilmes , Coenzimas , Escherichia coli , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Although metallacycle-based supramolecular photosensitizers (PSs) have attracted increasing attention in biomedicine, their clinical translation is still hindered by their inherent dark toxicity. Herein, we report what to our knowledge is the first example of a molecular engineering approach to building blocks of metallacycles for constructing a series of supramolecular PSs (RuA-RuD), with the aim of simultaneously reducing dark toxicity and enhancing phototoxicity, and consequently obtaining high phototoxicity indexes (PI). Detailed in vitro investigations demonstrate that RuA-RuD display high cancer cellular uptake and remarkable antitumor activity even under hypoxic conditions. Notably, RuD exhibited no dark toxicity and displayed the highest PI value (≈406). Theoretical calculations verified that RuD has the largest steric hindrance and the lowest singlet-triplet energy gap (ΔEST , 0.61â eV). Further in vivo studies confirmed that RuD allows safe and effective phototherapy against A549 tumors.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Neoplasias/tratamento farmacológicoRESUMO
Despite the success of emissive Ruthenium (Ru) agents in biomedicine, problems such as the visible-light excitation/emission and single chemo- or phototherapy modality still hamper their applications in deep-tissue imaging and efficient cancer therapy. Herein, an second nearinfrared window (NIR-II) emissive Ru(II) metallacycle (Ru1000, λem = 1000 nm) via coordination-driven self-assembly is reported, which holds remarkable deep-tissue imaging capability (≈6 mm) and satisfactory chemo-phototherapeutic performance. In vitro results indicate Ru1000 displays promising cellular uptake, good cancer-cell selectivity, attractive anti-metastasis properties, and remarkable anticancer activity against various cancer cells, including cisplatin-resistant A549 cells (IC50 = 3.4 × 10-6 m vs 92.8 × 10-6 m for cisplatin). The antitumor mechanism could be attributed to Ru1000-induced lysosomal membrane damage and mitochondrial-mediated apoptotic cell death. Furthermore, Ru1000 also allows the high-performance in vivo NIR-II fluorescence imaging-guided chemo-phototherapy against A549 tumors. This work may provide a paradigm for the development of long-wavelength emissive metallacycle-based agents for future biomedicine.
Assuntos
Neoplasias , Rutênio , Cisplatino/farmacologia , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imagem Óptica , Fototerapia/métodos , Nanomedicina Teranóstica/métodosRESUMO
Discrete Pt(II) metallacycles have potential applications in biomedicine. Herein, we engineered a dual-modal imaging and chemo-photothermal therapeutic nano-agent 1 that incorporates discrete Pt(II) metallacycle 2 and fluorescent dye 3 (emission wavelength in the second near-infrared channel [NIR-II]) into multifunctional melanin dots with photoacoustic signal and photothermal features. Nano-agent 1 has a good solubility, biocompatibility, and stability in vivo. Both photoacoustic imaging and NIR-II imaging in vivo confirmed that 1 can effectively accumulate at tumor sites with good signal-to-background ratio and favorable distribution. Guided by precise dual-modal imaging, nano-agent 1 exhibits a superior antitumor performance and less severe side effects compared with a single treatment because of the high efficiency of the chemo-photothermal synergistic therapy. This study shows that nano-agent 1 provides a promising multifunctional theranostic platform for potential applications in biomedicine.
Assuntos
Hipertermia Induzida , Raios Infravermelhos , Melaninas/química , Técnicas Fotoacústicas , Fototerapia , Platina/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Fluorescência , Camundongos Endogâmicos C57BL , Imagem Multimodal , Nanopartículas/química , Nanopartículas/ultraestrutura , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Fluorescent theranostics probes at the second near-IR region (NIR-II; 1.0-1.7 µm) are in high demand for precise theranostics that minimize autofluorescence, reduce photon scattering, and improve the penetration depth. Herein, we designed and synthesized an NIR-II theranostic nanoprobe 1 that incorporates a Pt(II) metallacycle 2 and an organic molecular dye 3 into DSPE-mPEG5000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000]). This design endows 1 with good photostability and passive targeting ability. Our studies show that 1 accurately diagnoses cancer with high resolution and selectively delivers the Pt(II) metallacycle to tumor regions via an enhanced permeability and retention effect. In vivo studies reveal that 1 efficiently inhibits the growth of tumor with minimal side effects. At the same time, improved fluorescent imaging quality and signal-to-noise ratios are shown due to the long emission wavelengths. These studies demonstrate that 1 is a potential theranostic platform for tumor diagnosis and treatment in the NIR-II region.
Assuntos
Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Animais , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/terapia , Fótons , Razão Sinal-RuídoRESUMO
Bacterial infection is one of the greatest threats to public health. In vivo real-time monitoring and effective treatment of infected sites through non-invasive techniques, remain a challenge. Herein, we designed a PtII metallacycle-based supramolecular photosensitizer through the host-guest interaction between a pillar[5]arene-modified metallacycle and 1-butyl-4-[4-(diphenylamino)styryl]pyridinium. Leveraging the aggregation-induced emission supramolecular photosensitizer, we improved fluorescence performance and antimicrobial photodynamic inactivation. In vivo studies revealed that it displayed precise fluorescence tracking of S. aureus-infected sites, and in situ performed image-guided efficient PDI of S. aureus without noticeable side effects. These results demonstrated that metallacycle combined with host-guest chemistry could provide a paradigm for the development of powerful photosensitizers for biomedicine.
Assuntos
Fármacos FotossensibilizantesRESUMO
Although metallacycle-based photosensitizers have attracted increasing attention in biomedicine, their clinical application has been hindered by their inherent dark toxicity and unsatisfactory phototherapeutic efficiency. Herein, we employ a π-expansion strategy for ruthenium acceptors to develop a series of Ru(ii) metallacycles (Ru1-Ru4), while simultaneously reducing dark toxicity and enhancing phototoxicity, thus obtaining a high phototoxicity index (PI). These metallacycles enable deep-tissue (â¼7 mm) fluorescence imaging and reactive oxygen species (ROS) production and exhibit remarkable anti-tumor activity even under hypoxic conditions. Notably, Ru4 has the lowest dark toxicity, highest ROS generation ability and an optimal PI (â¼146). Theoretical calculations verify that Ru4 exhibits the largest steric bulk and the lowest singlet-triplet energy gap (ΔE ST, 0.62 eV). In vivo studies confirm that Ru4 allows for effective and safe phototherapy against A549 tumors. This work thus is expected to open a new avenue for the design of high-performance metal-based photosensitizers for potential clinical applications.
RESUMO
Small molecule metal-based drugs have shown great achievements in preclinical and clinical applications. In particular, platinum based antitumor drugs are well established in current cancer chemotherapy. However, they face problems such as poor selectivity, severe toxicity and side effects, strong drug resistance, poor uptake/retention in vivo, and difficulty in monitoring the therapeutic effect in real time, which largely limit their widespread use in clinical applications. The metallacycles/metallacages formed by the coordination-driven self-assembly of highly emitting ligands can solve the above problems. Importantly, acceptors with chemotherapeutic properties in the metallacycles/metallacages can be combined with luminescent ligands to achieve a combination of chemotherapy, imaging contrast agents and multifunctional therapeutic platforms. Here, this review provides an insight into the paradigm of self-assembled metallacycles/metallacages in biological applications, from mono-chemotherapeutic drugs to excellent fluorescent imaging contrast agents and multifunctional therapeutic platforms.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Meios de Contraste , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Platina/uso terapêutico , Corantes Fluorescentes , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológicoRESUMO
Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications.
Assuntos
Antineoplásicos , Rutênio , Células A549 , Antineoplásicos/farmacologia , Apoptose , Cisplatino/farmacologia , Humanos , FototerapiaRESUMO
Due to the low autofluorescence and deep-photo penetration, the second near-infrared region fluorescence imaging technology (NIR-II, 1000-2000 nm) has been widely utilized in basic scientific research and preclinical practice throughout the past decade. The most attractive candidates for clinical translation are organic NIR-II fluorophores with a small-molecule framework, owing to their low toxicity, high synthetic repeatability, and simplicity of chemical modification. In order to enhance the translation of small molecule applications in NIR-II bioimaging, NIR-II fluorescence imaging technology has evolved from its usage in cells to the diagnosis of diseases in large animals and even humans. Although several examples of NIR-II fluorescence imaging have been used in preclinical studies, there are still many challenges that need to be addressed before they can finally be used in clinical settings. In this paper, we reviewed the evolution of the chemical structures and photophysical properties of small-molecule fluorophores, with an emphasis on their biomedical applications ranging from small animals to humans. We also explored the potential of small-molecule fluorophores.
Assuntos
Técnicas Biossensoriais , Animais , Corantes Fluorescentes/química , Humanos , Ionóforos , Imagem Óptica/métodosRESUMO
Herein, we construct a series of Ru(II) metallacycles with multimodal chemo-phototherapeutic properties, which exhibited much higher anticancer activity and better cancer-cell selectivity than cisplatin. The antitumor mechanism could be ascribed to the activation of caspase 3/7 and the resulting apoptosis. These results open new possibilities for Ru(II) metallacycles in biomedicine.
Assuntos
Antineoplásicos , Complexos de Coordenação , Neoplasias , Rutênio , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Humanos , Imidazóis/farmacologia , Ligantes , Neoplasias/tratamento farmacológico , Fototerapia , Rutênio/farmacologiaRESUMO
Ruthenium complexes are emerging as potential complements to platinum drugs. They also show promise as photo-diagnostic and therapeutic agents. However, most ruthenium species studied to date as potential drugs are characterized by short excitation/emission wavelengths. This limits their applicability for deep-tissue fluorescence imaging and light-based therapeutic treatments. Here, we report a Ru(ii) metallacycle (Ru1100) that emits at ≥1000 nm. This system possesses excellent deep-tissue penetration capability (â¼7 mm) and displays good chemo-phototherapeutic performance. In vitro studies revealed that Ru1100 benefits from good cellular uptake and produces a strong anticancer response against several cancer cell lines, including a cisplatin-resistant A549 cell line (IC50 = 1.6 µM vs. 51.4 µM for cisplatin). On the basis of in vitro studies, it is concluded that Ru1100 exerts its anticancer action by regulating cell cycle progression and triggering cancer cell apoptosis. In vivo studies involving the use of a nanoparticle formulation served to confirm that Ru1100 allows for high-performance NIR-II fluorescence imaging-guided precise chemo-phototherapy in the case of A549 tumour mouse xenografts with no obvious side effects. This work thus provides a paradigm for the development of long-wavelength emissive supramolecular theranostic agents based on ruthenium.
RESUMO
Photoacoustic imaging (PAI), which integrates the higher spatial resolution of optical imaging and the deeper penetration depth of ultrasound imaging, has attracted great attention. Various photoacoustic probes including inorganic and organic agents have been well fabricated in last decades. Among them, small-molecule based agents are most promising candidates for preclinical/clinical applications due to their favorite in vivo features and facile functionalization. In recent years, PAI, in the near-infrared region (NIR, 700-1700 nm) has developed rapidly and has made remarkable achievements in the biomedical field. Compared with the visible light region (400-700 nm), it can significantly reduce light scattering and meanwhile provide deeper tissue penetration. In this review, we discuss the recent developments of near-infrared photoacoustic probes based on small molecule dyes, which focus on their "always on" and "activatable" form in biomedicine. Further, we also suggest current challenges and perspectives.
RESUMO
Despite the wide application of the traditional NIR-I phototheranostic platforms in basic research and clinical studies, problems such as tissue scattering, auto-fluorescence combined with aggregation caused quenching hamper precise image-guided phototherapy. Herein, we developed a multifunctional NIR-II phototheranostic platform using a novel AIE-based dye (ZSY-TPE) for single laser-activated imaging-guided combined photothermal and photodynamic therapies of tumors and pathogens. As confirmed through in vivo studies, the ZSY-TPE dots displayed precise and efficient high-performance NIR-II imaging-guided combination phototherapy against 4T1 tumor as well as S. aureus-infected mice models without any noticeable side effects. The current study demonstrates ZSY-TPE as a powerful phototheranostic platform for precise NIR-II fluorescence/PA imaging and synergistic photodynamic/photothermal therapy of tumors and bacterial infections.